This sequence change affects an acceptor splice site in intron 3 of the AMN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMN are known to be pathogenic (PMID: 12590260, 22929189). This variant is present in population databases (rs386834170, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Imerslund-GraÃàsbeck Syndrome (PMID: 12590260, 22078000, 24044590, 32045704). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56751). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_030943.4(AMN):c.208-2A>G
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_030943.4(AMN):c.208-2A>G
Variation ID: 56751 Accession: VCV000056751.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q32.32 14: 102928424 (GRCh38) [ NCBI UCSC ] 14: 103394761 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 24, 2013 Oct 20, 2024 Mar 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_030943.4:c.208-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000014.9:g.102928424A>G NC_000014.8:g.103394761A>G NG_008276.2:g.10769A>G LRG_642:g.10769A>G LRG_642t1:c.208-2A>G - Protein change
- -
- Other names
-
IVS3, A-G, -2
- Canonical SPDI
- NC_000014.9:102928423:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 30x 0.00031
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CDC42BPB | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
231 | 302 | |
| AMN | - | - |
GRCh38 GRCh37 |
460 | 639 | |
| LOC130056553 | - | - | - | GRCh38 | - | 49 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000005037.8 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Dec 28, 2023 | RCV000050164.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 21, 2020 | RCV001280864.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2023 | RCV001815177.20 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Imerslund-Grasbeck syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004302065.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 3 of the AMN gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 3 of the AMN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMN are known to be pathogenic (PMID: 12590260, 22929189). This variant is present in population databases (rs386834170, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Imerslund-GraÃàsbeck Syndrome (PMID: 12590260, 22078000, 24044590, 32045704). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56751). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002063389.20
First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024 |
Comment:
AMN: PVS1, PM2, PM3
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Imerslund-Grasbeck syndrome type 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573008.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000056751). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Anemia (present) , Thrombocytopenia (present) , Nephrotic range proteinuria (present)
|
|
|
Pathogenic
(Nov 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Imerslund-Grasbeck syndrome type 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813825.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Imerslund-Grasbeck syndrome type 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004801900.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Clinical Features:
Proteinuria (present) , Hyperbilirubinemia (present) , Abnormality of vitamin B12 metabolism (present) , Premature adrenarche (present) , Abnormal circulating vitamin B12 concentration (present) , Cobalamin … (more)
Proteinuria (present) , Hyperbilirubinemia (present) , Abnormality of vitamin B12 metabolism (present) , Premature adrenarche (present) , Abnormal circulating vitamin B12 concentration (present) , Cobalamin deficiency (present) (less)
|
|
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probable-pathogenic
(-)
|
no assertion criteria provided
Method: not provided
|
Megaloblastic anemia due to inborn errors of metabolism
Affected status: not provided
Allele origin:
not provided
|
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082574.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
|
Comment:
Converted during submission to Likely pathogenic.
|
|
|
Pathogenic
(Jan 01, 2007)
|
no assertion criteria provided
Method: literature only
|
IMERSLUND-GRASBECK SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025213.2
First in ClinVar: Apr 04, 2013 Last updated: May 31, 2020 |
Comment on evidence:
In a Tunisian Jewish family (family M) with Imerslund-Grasbeck syndrome-2 (IGS2; 618882), Tanner et al. (2003) identified a homozygous A-to-G transition in intron 3 (c.208-2A-G) … (more)
In a Tunisian Jewish family (family M) with Imerslund-Grasbeck syndrome-2 (IGS2; 618882), Tanner et al. (2003) identified a homozygous A-to-G transition in intron 3 (c.208-2A-G) of the AMN gene, predicted to result in a splice site alteration. RT-PCR analysis showed that this splice mutation caused complete skipping of exon 4 (88 bp) with a subsequent frameshift and premature termination in exon 6. Bouchlaka et al. (2007) reported a Tunisian family with IGS2 caused by a homozygous c.208-2A-G mutation in the AMN gene. Since the mutation had previously been reported in a Jewish Israeli family of Tunisian origin and in Turkish families, the authors suggested a founder effect originating in the Mediterranean basin. In 3 children from 2 unrelated consanguineous families of Turkish (family 1) and Tunisian (family 2) origin with IGS2, Storm et al. (2013) identified a homozygous c.208-2A-G mutation in the AMN gene. Two sibs from another family (family 4) of Italian descent were compound heterozygous for c.208-2A-G and a 3-bp del/ins mutation in exon 10 (c.1041_1042delinsCTC; 605799.0004). The latter mutation was predicted to result in an aberrant and elongated transcript that would likely cause an unstable protein and a functionally null allele. The variant was not found in 166 control alleles. (less)
|
|
|
Pathogenic
(Jan 21, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Imerslund-Grasbeck syndrome type 1
Affected status: yes
Allele origin:
germline
|
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV001468209.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Megaloblastic anemia due to inborn errors of metabolism
Affected status: not provided
Allele origin:
unknown
|
Inserm U 954, Faculté de Médecine de Nancy
Accession: SCV000243929.1
First in ClinVar: Aug 15, 2015 Last updated: Aug 15, 2015
Comment:
Namour F, Dobrovoljski G, Chery C, Audonnet S, Feillet F, Sperl W, Gueant JL. Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound … (more)
Namour F, Dobrovoljski G, Chery C, Audonnet S, Feillet F, Sperl W, Gueant JL. Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica. 2011 Nov;96(11):1715-9. doi: 10.3324/haematol.2011.043984. (less)
|
|
Comment:
Comment:
AMN: PVS1, PM2, PM3
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000056751). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Likely pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change affects an acceptor splice site in intron 3 of the AMN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AMN are known to be pathogenic (PMID: 12590260, 22929189). This variant is present in population databases (rs386834170, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Imerslund-GraÃàsbeck Syndrome (PMID: 12590260, 22078000, 24044590, 32045704). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56751). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
AMN: PVS1, PM2, PM3
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000056751). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Imerslund-Gräsbeck Syndrome presenting with microangiopathic hemolytic anemia in a child. | Gurlek Gokcebay D | European journal of medical genetics | 2020 | PMID: 32045704 |
| Detailed investigations of proximal tubular function in Imerslund-Gräsbeck syndrome. | Storm T | BMC medical genetics | 2013 | PMID: 24156255 |
| Imerslund-Gräsbeck syndrome in a 25-month-old Italian girl caused by a homozygous mutation in AMN. | De Filippo G | Italian journal of pediatrics | 2013 | PMID: 24044590 |
| Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. | Tanner SM | Orphanet journal of rare diseases | 2012 | PMID: 22929189 |
| Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities. | Beech CM | Orphanet journal of rare diseases | 2011 | PMID: 22078000 |
| Genetic heterogeneity of megaloblastic anaemia type 1 in Tunisian patients. | Bouchlaka C | Journal of human genetics | 2007 | PMID: 17285242 |
| Imerslund-Grasbeck syndrome associated with recurrent aphthous stomatitis and defective neutrophil function. | Broides A | Journal of pediatric hematology/oncology | 2006 | PMID: 17114957 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. | Tanner SM | Human mutation | 2004 | PMID: 15024727 |
| Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. | Tanner SM | Nature genetics | 2003 | PMID: 12590260 |
Text-mined citations for rs386834170 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.